High concentration dinotefuran formulations

ABSTRACT

A topical insecticide is provided which can be safe to use and avoids many common deleterious side effects of conventional topical insecticides. In one preferred embodiment of the invention, the active ingredient of the insecticide formulation is an amine derivative, having a nitro-methylene group, a nitroamino group or a cyanoamino group, which can be formulated to have low toxicity and excellent insecticidal activity. One particularly suitable insecticide is 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran), an aldulticide that will kill adult fleas dissolved in ethyl lactate.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. Ser. No.10/411,720, filed Apr. 11, 2003, which is a continuation-in-part of U.S.Ser. No. 10/242,550, now U.S. Pat. No. 6,588,374, U.S. Ser. No.10/242,551, now U.S. Pat. No. 6,867,223 and U.S. Ser. No. 10/242,552,now U.S. Pat. No. 6,814,030, all of which were filed Sep. 12, 2002.Priority is claimed to all of the applications listed above, which areincorporated herein by reference.

BACKGROUND OF INVENTION

The invention relates generally to insecticides and more particularly toa topical insecticide, such as one suitable to use on house pets such ascats and dogs.

The infestation of animals with fleas, ticks, flies and the like ishighly undesirable. Accordingly, it has become common to administer bothtopical and internal insecticides to livestock and pets. Topicalapplications can be desirable, in that many insecticides are acceptablysafe when used topically, but not when used internally.

Various topical insecticides have drawbacks. Some require a large volumeto be applied to the animal. This can cause considerable mess and canlead to an unpleasant smell. Others use irritating or foul smellingsolvents. Also, when the animal is a house pet, there is a furthercomplication in that the insecticide should be safe for human contact.It should also not lead to staining of furniture, carpeting and thelike. Finally, even if safe, topical insecticides for house pets shouldnot be irritating or lead to rashes, hair loss or exhibit otherunpleasant side effects.

Accordingly, it is desirable to provide an improved topical insecticide,which overcomes drawbacks of the prior art.

SUMMARY OF THE INVENTION

Generally speaking, in accordance with the invention, a topicalinsecticide is provided which can be safe to use and avoids many commondeleterious side effects of conventional topical insecticides. In onepreferred embodiment of the invention, the active ingredient of theinsecticide formulation is an amine derivative, having a nitro-methylenegroup, a nitroamino group or a cyanoamino group, which can be formulatedto have low toxicity and excellent insecticidal activity. Activeingredients of insecticides and their method of formation in accordancewith the preferred embodiments of the invention are discussed in U.S.Pat. Nos. 5,434,181, 5,532,365, 6,588,374, 6,814,030 and 6,867,223 andU.S. application Ser. No. 10/411,720 filed on Apr. 11, 2003, thecontents of which are incorporated herein by reference. One particularlysuitable insecticide is1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine(dinotefuran). Dinotefuran is an aldulticide that will kill adult fleas.

In one preferred embodiment of the invention, the active portion of theinsecticide formulation comprises (tetrahydro-3-furanyl)methylaminederivatives of following formula (1):

Active ingredients and insecticides in accordance with preferredembodiments of the invention are generally available as crystals andsolids. Therefore, they need to be dissolved or otherwise put into aliquid form for use as topical spot products on animals. Topical spotproducts are more advantageous if the amount of liquid applied can beminimized. This must be balanced with the need for appropriate dosage toachieve the desired insecticidal effect. Therefore, it is desirable touse a solvent that will allow the solubilization of a high concentrationof insecticide. It has been determined that ethyl lactate is aparticularly useful solvent for forming dinotefuran containingcompositions. Compositions containing ethyl lactate in combination withwater and/or alcohols are also advantageous.

It is also desirable that the resulting formulation be stable. Forexample, it should not exhibit crystallization when stored at 0° F. and40° F. for 1 month and longer. This is important because theseconditions can be met in commerce. The crystallization would reduce theamount of insecticide in solution and reduce the efficacy of thesolution applied to the animal.

Phenyl methanol is an alcohol, also known as benzyl alcohol, and is aliquid, somewhat soluble in water. It was surprisingly discovered that arelatively high concentration of the dinotefuran can be solubilized inphenyl methanol.

Methoprene is an insecticide that acts as an insect growth regulatorthat prevents flea eggs from hatching. It was unexpectedly determinedthat methoprene can act as a solubility enhancer for amine derivativeinsecticides such as dinotefuran, discussed above. For example, theaddition of methoprene to the dinotefuran formulations with phenylmethanol allowed the preparation of more highly concentrated solutionsof dinotefuran that do not crystallize at 0° F.

In one aspect of the current invention, the dinotefuran is dissolved insolvent containing methoprene to a concentration range of 5-25%, morepreferably 9-20% and most preferably about 12.5 to 19.2%, with 17.5% asa preferred example. All percentages, unless otherwise evident, are on aweight basis.

The formulation can be applied as a topical drop about once per month,preferably in the area between the shoulder blades and the base of theskull to kill fleas and flea eggs for over a one month period.

Accordingly, it is an object of the invention to provide an improvedtopical insecticide, which overcomes drawbacks of the prior art.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The novel (tetrahydro-3-furanyl)methylamine derivatives of the formula(1) have an excellent insecticidal activity even in the absence of apyridylmethyl group or a thiazolylmethyl group in their molecularstructure. According to the present invention, there are provided(tetrahydro-3-furanyl)methylamine derivatives represented by formula(1), where X₁, X₂, X₃, X₄, X₅, X₆ and X₇ represent each a hydrogen atomor an alkyl group having from 1 to 4 carbon atoms; R₁ represents ahydrogen atom, an alkyl group having from 1 to 5 carbon atoms, analkenyl group having 3 carbon atoms, a benzyl group, an alkoxyalkylgroup having from 2 to 4 carbon atoms (in its whole group), analkyloxycarbonyl group having from 1 to 3 carbon atoms, a phenoxycarbonyl group, an alkylcarbonyl group having from 1 to 6 carbon atoms,an alkenylcarbonyl group having from 2 to 3 carbon atoms, acycloalkylcarbonyl group having from 3 to 6 carbon atoms, a benzoylgroup, a benzoyl group substituted by alkyl group(s) having from 1 to 4carbon atoms, a benzoyl group substituted by halogen atom(s), a2-furanylcarbonyl group or an N,N-dimethylcarbamoyl group; R₂ representsa hydrogen atom, an amino group, a methyl group, an alkylamino grouphaving from 1 to 5 carbon atoms, a di-substituted alkylamino grouphaving from 2 to 5 carbon atoms (in its whole group), a 1-pyrrolidinylgroup, an alkenylamino group having 3 carbon atoms, an alkynylaminogroup having 3 carbon atoms, a methoxyamino group, an alkoxyalkylaminogroup having from 2 to 4 carbon atoms (in its whole group), a methylthiogroup or —N(Y₁)Y₂ (where Y₁ represents an alkyloxycarbonyl group havingfrom 1 to 3 carbon atoms, a phenoxycarbonyl group, an alkylcarbonylgroup having from 1 to 6 carbon atoms, an alkenylcarbonyl group havingfrom 2 to 3 carbon atoms, a cycloalkylcarbonyl group having from 3 to 6carbon atoms, a benzoyl group, a benzoyl group substituted by alkylgroup(s) having from 1 to 4 carbon atoms, a benzoyl group substituted byhalogen atom(s), a 2-furanylcarbonyl group, an N,N-dimethylcarbamoylgroup, a (tetrahydro-3-furanyl)methyl group or a benzyl group, and Y₂represents a hydrogen atom or an alkyl group having from 1 to 5 carbonatoms); and Z represents ═N—NO₂, ═CH—NO₂ or ═N—CN; insecticidescontaining the derivatives as an effective ingredient; and intermediatesfor producing the compounds of the formula (1) represented by a formula(2):

where X₁, X₂, X₃, X₄, X₅, X₆ and X₇ represent each a hydrogen atom or analkyl group having from 1 to 4 carbon atoms; R₁₀ represents an alkylgroup having from 1 to 5 carbon atoms or a benzyl group; and R₁₁represents an alkyl group having from 1 to 5 carbon atoms or a benzylgroup.

The (tetrahydro-3-furanyl)methylamine derivatives of the formula (1) andformula (2) according to the invention have a high insecticidal powerand broad insecticidal spectrum. Further, agricultural chemicalscontaining the (tetrahydro-3-furanyl)methylamine derivatives of theformula (1) and (2) according to the invention have outstandingcharacteristics as insecticides and hence are useful.

Specific examples of the alkyl group for X₁, X₂, X₃, X₄, X₅, X₆ and X₇in the above formulae (1) and (2) include a methyl group, an ethylgroup, an n-propyl group, an iso-propyl group, a tert-butyl group, andthe like, preferably a methyl group.

Specific examples of the alkyl group for R₁ include a methyl group, anethyl group, an n-propyl group, an iso-propyl group, an n-butyl group,an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentylgroup, and the like.

Specific examples of the alkenyl group for R₁ include a 1-propenylgroup, a 2-propenyl group, and the like.

Specific examples of the alkoxyalkyl group for R₁ include amethoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, aniso-propoxymethyl group, a methoxyethyl group, an ethoxyethyl group, andthe like.

Specific examples of the alkyloxycarbonyl group for R₁ include amethyloxycarbonyl group, an ethyloxycarbonyl group, ann-propyloxycarbonyl group, an iso-propyloxycarbonyl group, and the like.

Specific examples of the alkylcarbonyl group for R₁ include amethylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group,an iso-propylcarbonyl group, an n-butylcarbonyl group, aniso-butylcarbonyl group, a sec-butylcarbonyl group, a tert-butylcarbonylgroup, an n-pentylcarbonyl group, an n-hexylcarbonyl group, and thelike.

Specific examples of the alkenylcarbonyl group for R₁ include avinylcarbonyl group, a 1-methylvinylcarbonyl group, and the like.

Specific examples of the cycloalkylcarbonyl group for R₁ include acyclopropylcarbonyl group, a cyclobutylcarbonyl group, acyclopentylcarbonyl group, a cyclohexylcarbonyl group, and the like.

Specific examples of the benzoyl group substituted by alkyl group(s) forR₁ include a 2-methylbenzoyl group, a 3-methylbenzoyl group, a4-methylbenzoyl group, a 4-tert-butylbenzoyl group, and the like.

Specific examples of the benzoyl group substituted by halogen atom(s)for R₁ include a 2-chlorobenzoyl group, a 3-chlorobenzoyl group, a4-chlorobenzoyl group, a 3,4-dichloro-benzoyl group, a 4-fluorobenzoylgroup, and the like.

Although R₁ can take various substituents as described above, it ispreferably a hydrogen atom, an alkylcarbonyl group having from 1 to 4carbon atoms or a cyclopropylcarbonyl group.

Specific examples of the alkylamino group for R₂ include a methylaminogroup, an ethylamino group, an n-propyl-amino group, an iso-propylaminogroup, an n-butylamino group, an iso-butylamino group, a sec-butylaminogroup, a tert-butylamino group, an n-pentylamino group, and the like,preferably a methylamino group.

Specific examples of the di-substituted alkylamino group for R₂ includea dimethylamino group, a diethylamino group, an N-methyl-N-ethylaminogroup, an N-methyl-N-n-prpylamino group, an N-methyl-N-n-butylaminogroup, and the like, preferably a dimethylamino group.

Specific examples of the alkenylamino group for R₂ include a1-propenylamino group, a 2-propenylamino group, and the like.

Specific examples of the alkynylamino group for R₂ include apropargylamino group, and the like.

Specific examples of the alkoxyalkylamino group for R₂ include amethoxymethylamino group, an ethoxymethylamino group, ann-propoxymethylamino group, an iso-propoxymethylamino group, amethoxyethylamino group, an ethoxyethylamino group, and the like.

Specific examples of the alkyloxycarbonyl group denoted by Y₁ for R₂include a methyloxycarbonyl group, an ethyloxy-carbonyl group, ann-propyloxycarbonyl group, an iso-propyloxy-carbonyl group, and thelike.

Specific examples of the alkylcarbonyl group denoted by Y₁, for R₂include a methylcarbonyl group, an ethylcarbonyl group, ann-propylcarbonyl group, an iso-propylcarbonyl group, an n-butylcarbonylgroup, an isobutylcarbonyl group, a sec-butyl-carbonyl group, atertbutylcarbonyl group, an n-pentylcarbonyl group, an n-hexylcarbonylgroup, and the like, preferably a methylcarbonyl group, an ethylcarbonylgroup, an n-propylcarbonyl group, an iso-propylcarbonyl group, ann-butylcarbonyl group, an iso-butylcarbonyl group, a sec-butylcarbonylgroup and a tert-butylcarbonyl group.

Specific examples of the alkenylcarbonyl group denoted by Y₁, for R₂include a vinylcarbonyl group, a 1-methyl-vinylcarbonyl group, and thelike.

Specific examples of the cycloalkylcarbonyl group denoted by Y₁, for R₂include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, acyclopentylcarbonyl group, a cyclo-hexylcarbonyl group, and the like,preferably a cyclopropyl-carbonyl group.

Specific examples of the benzoyl group substituted by alkyl group(s)denoted by Y₁, for R₂ include a 2-methylbenzoyl group, a 3-methylbenzoylgroup, a 4-methylbenzoyl group, a 4-tert-butylbenzoyl group, and thelike.

Specific examples of the benzoyl group substituted by halogen atom(s)denoted by Y₁, for R₂ include a 2-chlorobenzoyl group, a 3-chlorobenzoylgroup, a 4-chlorobenzoyl group, a 3,4-dichlorobenzoyl group, a 4-fluorobenzoyl group, and the like.

Specific examples of the alkyl group denoted by Y₂ for R₂ include amethyl group, an ethyl group, an n-propyl group, an iso-propyl group, ann-butyl group, an iso-butyl group, a sec-butyl group, a tert-butylgroup, an n-pentyl group, and the like, preferably a methyl group.

In the formula (1), compounds in which R₁ and Y₁ are concurrently analkylcarbonyl group having from 1 to 4 carbon atoms or acyclopropylcarbonyl group are preferred from the viewpoint of bothinsecticidal activity and production method.

In the development of a formulation for use on animals, there areseveral parameters that should be considered. These include:

-   -   (a) Concentration high enough to minimize the volume of the        topical applied to the animal (e.g., one would not want to put        20 ml onto a small cat).    -   (b) The formulation should be stable for one month at 130° F.,        110° F., 40° F., room temperature and 0° F. This helps ensure        that the formulation remains stable under the conditions that it        could meet in commerce.    -   (c) Safe to use on the animal—particularly non-irritating since        the product is applied to the skin. Also safe if ingested by the        animal; ingestion can occur when cats groom themselves.    -   (d) Safe to use by the consumer.    -   (e) Stable and efficacious in use—should kill greater than 90%        of the fleas up to 28 days.    -   (f) Efficacy would be reduced if crystallization occurred in the        package.    -   (g) Aesthetically pleasing.    -   (h) Fast drying to reduce the chance of the animal shaking off        the liquid thereby reducing efficacy.    -   (i) Microbiologically stable.

U.S. Pat. Nos. 5,434,181 and 5,532,365 recognize different possiblesolvents, but do not provide information on how to formulate theinsecticide in a non-irritating manner. No examples were given in whichthe compounds were used on animals. Additionally, in all of the examplesgiven, the compounds were dissolved into solvents that are undesirableto use on animals. Specifically, acetone, used in all but one of theexamples, is very irritating by both inhalation and skin contact, due tode-fatting action on skin and mucous membranes. It is also veryirritating to the eyes. Accordingly, there is a need to develop adifferent solvent for these compounds that can be used on animals. Thepresent invention can satisfy the parameters detailed above.

In one aspect of the current invention, the dinotefuran is dissolved insolvent containing methoprene to a concentration range of 5-25%, morepreferably 9-20% and most preferably about 12.5 to 19.2%, with 17.5% asa preferred example. All percentages, unless otherwise evident, are on aweight basis. Methoprene is advantageously included as over 0.1%,advantageously about 0.1 to 3%. Advantageous weight ratios ofdinotefuran:methoprene range from about 30:1 to 2.5:1, more preferablyabout 25:1 to 3:1.

Pyriproxyfen is an insect growth regulator that prevents fleas fromhatching. It was unexpectedly determined that pyriproxyfen can act as asolubility enhancer for the amine derivative insecticides such asdinotefuran, discussed herein. For example, the addition of pyriproxyfento the dinotefuran formulations with phenyl methanol allowed thepreparation of more highly concentrated solutions of dinotefuran that donot crystallize at 0° F.

In another aspect of the present invention, the dinotefuran can bedissolved in solvent containing pyriproxyfen to a concentration range of5-25%, more preferably 9-20% and most preferable about 12.5-19.2% with17.5% as a preferred example. Pyriproxyfen is advantageously included asover 0.1%, advantageously about 0.1 to 3%.

In another embodiment of the present invention, the solvent componentcan contain ethyl lactate. It can be a mixture comprising water, ethyllactate and alcohol, preferably ethanol. The final concentration ofethyl lactate can range from 5-20%. The final concentration of ethanolcan range from 30-45%; more preferably 7-15% ethyl lactate and 35-43%ethanol and most preferable to a final concentration of 10% ethyllactate and 40% ethanol. The remainder can be water. Isopropanol canalso be added to ethanol to improve solubility.

It has been found that when the solvent comprises phenyl methanol or acombination of ethyl lactate and ethanol, higher concentrations ofactive ingredient can be incorporated. In one aspect of the currentinvention, the active compound is dissolved in solvent to aconcentration range of 2-20%, more preferably 4-17% and most preferablyabout 8 to 14%, with 12.5% as a preferred example. All percentages,unless otherwise evident, are on a weight basis.

In another preferred embodiment of the invention, the preferred solventcomponent comprises a mixture comprising water, ethyl lactate andethanol, wherein the final concentration of ethyl lactate ranges from5-20% and the final concentration of ethanol ranges from 30-45%, morepreferably 7-15% ethyl lactate and 35-43% ethanol and most preferable afinal concentration of 10% ethyl lactate and 40% ethanol. The remaindercan be water. Isopropanol can also be added to ethanol to improvesolubility.

In another aspect of the present invention, the dinotefuran can bedissolved in a solvent component comprising ethyl lactate. The solventcomponent can consist essentially of ethyl lactate and water. The finalconcentration of ethyl lactate can range from about 35-57%; morepreferably about 42-53% and most preferable about 47.5-50% with 48.6% asa preferred example. The final concentration of dinotefuran can rangefrom about 5-25%, more preferably about 7-21% and most preferably about12-17%, with 15% as a preferred example.

In one embodiment of the invention, the preferred solvent componentcomprises a mixture comprising water and ethanol at a concentrationrange of 50-80% ethanol, more preferably 65-75% ethanol and mostpreferably about 69-71% ethanol, with a preferred example 70% ethanol.The remainder can be water. The insecticide formulation can includevarious additions to the ethanol/water combination.

In another embodiment of the invention, the preferred solvent componentcomprises a mixture comprising water, ethanol and isopropanol, whereinthe final concentration of total alcohol range from 50-80% alcohol, morepreferably 65-75% alcohol and most preferably about 69-71% alcohol, witha preferred example 70% alcohol. The remainder can be water. Theconcentration of ethanol and isopropanol are 25-45% ethanol, 25-45%isopropanol, more preferably 30-40% ethanol, 30-40% isopropanol and mostpreferably 35% ethanol and 35% isopropanol.

In another embodiment of the invention, the solvent comprises a mixturecomprising dipropyleneglycol monomethyl ether (DPM) and water at aconcentration range of about 30-70% DPM, more preferably about 45-55%DPM and most preferably about 50% DPM/50% water mixture.

In yet another embodiment of the invention, the preferred solvent is amixture comprising water, ethanol and DPM at a concentration range of25-40% ethanol, 25-40% DPM, more preferably 30-35% ethanol, 30-35% DPMand most preferably equal volumes of each component (i.e., 33% ethanol,33% DPM and 33% water).

In one aspect of the current invention, the compound is dissolved insolvent to a concentration range of 2-15%, more preferably 4-9% and mostpreferably about 5 to 8%, with 6% as a preferred example. Allpercentages, unless otherwise evident, are on a weight basis.

In one embodiment of the invention, the preferred solvent componentcomprises a mixture comprising water and an alcohol, preferably ethanol,at a concentration range of 50-80% ethanol, more preferably 65-75%ethanol and most preferably about 69-71% ethanol, with a preferredexample 70% ethanol. The remainder can be water. The insecticideformulation can include various additions to the ethanol/watercombination.

In another embodiment of the invention, the preferred solvent componentcomprises a mixture comprising water, ethanol and isopropanol, whereinthe final concentration of total alcohol range from 50-80% alcohol, morepreferably 65-75% alcohol and most preferably about 69-71% alcohol, witha preferred example 70% alcohol. The remainder can be water. Theconcentration of ethanol and isopropanol are 25-45% ethanol, 25-45%isopropanol, more preferably 30-40% ethanol, 30-40% isopropanol and mostpreferably 35% ethanol and 35% isopropanol.

In another embodiment of the invention, the preferred solvent comprisesa mixture comprising dipropyleneglycol monomethyl ether (DPM) and waterat a concentration range of about 30-70% DPM, more preferably about45-55% DPM and most preferably about 50% DPM/50% water mixture.

In yet another embodiment of the invention, the preferred solvent is amixture comprising water, ethanol and DPM at a concentration range of25-40% ethanol, 25-40% DPM, more preferably 30-35% ethanol, 30-35% DPMand most preferably equal volumes of each component (i.e., 33% ethanol,33% DPM and 33% water).

It will be readily appreciated by the skilled artisan that theformulations described herein may also comprise additives including, butnot limited to, fragrances, hair conditioners, solvation aids, spreadingagents, solubilizers and UV protectants.

The formulation can be applied as a topical drop about once per month,preferably in the area between the shoulder blades and the base of theskull to kill fleas and flea eggs for over a one month period. In theembodiments of the present invention described herein, up to 20 ml ofthe formulation can be applied to the animal, with about 1.0 ml being amore typical application to kill fleas and flea eggs for over a onemonth period. In certain embodiments of the invention, as application ofabout 0.4 ml can be sufficient to kill fleas and flea eggs for over aone month period.

The following examples are given for purposes of illustration only andare not intended to be construed in a limiting manner.

EXAMPLE 1 Preparation of1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran)

A mixture comprising 10.0 g of (tetrahydro-3-furanyl)methanol, 29.5 g oftrifluoromethanesulfonic anhydride, 10.0 g of pyridine and 200 ml ofdichloromethane was stirred for an hour at room temperature. Water waspoured into the reaction solution to separate the organic layer, whichwas washed with 1 N hydrochloric acid, water and a saturated salinesolution, dried, and concentrated to obtain 20 g of3-tetrahydro-furanylmethyl triflate. 3.25 g of 60% sodium hydride wereadded to 12.5 g of 1,5-dimethyl-2-nitroiminohexahydro-1,3,5-triazine and60 ml of DMF at room temperature, followed by stirring for an hour. 20.0g of the 3-tetrahydrofuranylmethyl triflate were added thereto, and themixture was stirred at 50° C. for 2 hours. After cooling the mixture toroom temperature, 50 ml of 2N hydrochloric acid were added thereto,followed by stirring at 500° C. for 2hours. The resultant mixture wasneutralized with sodium bicarbonate and extracted with dichloromethane,and the extract was dried and concentrated. The residue thus obtainedwas purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/1) to obtain 7.8 g of1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine(dinotefuran).

EXAMPLE 2 Preparation of Insecticide Formulation Containing Dinotefuran,Ethanol and Water

5 g (i.e., 5.6% (weight/weight)) of dinotefuran was dissolved into 100ml of a mixture comprising 70% ethanol and 30% water. The resultingmixture can be spot applied to companion animals, such as dogs and catsand will kill fleas, ticks and other insects.

EXAMPLE 3 Preparation of Insecticide Formulation Containing Dinotefuranand Phenyl Methanol

15 g (i.e., 12.5% (weight/weight)) of dinotefuran was dissolved into 100ml of phenyl methanol. The resulting solution can be spot applied tocompanion animals, such as dogs and cats and will kill fleas, ticks andother insects.

EXAMPLE 4 Preparation of Insecticide Formulation Containing Dinotefuran,Pyriproxyfen and Phenyl Methanol

20 g of dinotefuran was added to 100 ml phenyl methanol with stirringuntil it dissolves. 3 g of pyriproxyfen was added to the solution withstirring to produce a clear, homogeneous solution.

EXAMPLE 5 Preparation of Insecticide Formulation Containing Dinotefuran,Pyriproxyfen and Phenyl Methanol

25 g of dinotefuran was added to 100 ml phenyl methanol with stirringuntil it dissolved. 1 g of pyriproxyfen was added to the solution withstirring to produce a clear, homogeneous solution of high insecticideconcentration.

The resulting solution can be spot applied to companion animals, such asdogs and cats and will kill fleas, ticks and other insects.

EXAMPLE 6 Stability of Dinotefuran/Pyridproxyfen Formulations

Table 1 demonstrates that an approximate 50% increase in concentrationcan be achieved for dinotefuran by including pyriproxyfen at low levelsin the formulation based on the criterion of no crystal formation at 0°F. during a 1 month period. TABLE 1 Formulation Stability Studies (% arew/w) Dinotefuran Pyriproxyfen Phenyl Methanol Stable 12.5 0 87.5 Yes14.7 0 85.3 No* 15.7 2.4 81.9 Yes 15.9 0.8 83.3 Yes 19.2 0.8 80.0 Yes*Crystallizes at 0° F.

EXAMPLE 7 Preparation of Insecticide Formulation Containing Dinotefuran,Methoprene and Phenyl Methanol

20 g of dinotefuran was added to 100 ml phenyl methanol with stirringuntil it dissolved. 1 g of methoprene was added to the solution withstirring to produce a clear, homogeneous solution of high insecticideconcentration.

EXAMPLE 8 Preparation of Insecticide Formulation Containing Dinotefuran,Methoprene and Phenyl Methanol

18 g of dinotefuran was added to 100 ml phenyl methanol with stirringuntil it dissolved. 1 g of methoprene was added to the solution withstirring to produce a clear, homogeneous solution of high insecticideconcentration.

EXAMPLE 9 Preparation of Insecticide Formulation Containing DinotefuranMethoprene and Phenyl Methanol

16 g of dinotefuran was added to 100 ml phenyl methanol with stirringuntil it dissolved. 1 g of methoprene was added to the solution withstirring to produce a clear, homogeneous solution of high insecticideconcentration.

EXAMPLE 10 Stability of Dinotefuran/Methoprene Formulations

TABLE 2 Formulation Stability Studies (% are w/w) Dinotefuran MethoprenePhenyl Methanol Stable 12.5 0 87.5 Yes 14.7 0 85.3 No* 19.2 0.8 80.0 No*18.5 0.8 80.7 Yes 17.5 0.8 81.7 Yes 16.0 0.8 83.2 Yes 14.6 0.8 84.6 Yes12.9 3.2 83.9 Yes 12.1 4.0 83.9 Yes*Crystallizes at 0° F.

It has been determined that the concentration of dinotefuran can beincreased up to 50% and more by including methoprene, even at low levelsof about 0.8% and below, compared to a similar formulation withoutmethoprene. Also, inclusion of methoprene up to and over 4% are stable.Typically, dinotefuran concentration of over about 8% will crystallizeat 0° F. within a few days.

EXAMPLE 11 In Vivo Activity of a Flea Dermal Treatment Against the CatFlea (Ctenocephalides felis) on Cats

Eighteen cats were separated into three groups each containing 6 cats.Group 1 (6cats each weighing 9 lbs. or less) remained untreated asNon-Treated Controls. Group 2 (6 cats each over 9 lbs.) were treatedwith 3.4 ml of the dinotefuran insecticide formulation (5.71% w/w).Group 3 (6 cats each weighing 9 lbs. or less) were treated with 1.5 mlof the dinotefuran insecticide formulation (5.71% w/w).

Approximately 18 hours prior to treatment the cats were infested with100 cat fleas (Ctenocephalides felis) which were applied to the animal'sback. Cats in Groups 2 and 3 were then treated with the indicated volumeof insecticide by dispensing the liquid at skin level between theshoulder blades. Flea counts were taken at day 1 (i.e., 24 hourspost-treatment), day 8, day 15, day 22 and day 29.Cats were re-infestedwith 100 fleas on days 7, 14, 21,and 28.To determine the efficacy of thedermal treatment, the number of fleas found on treated cats was comparedto the number of fleas found on untreated cats. Percent reduction wasdetermined as follows and the results are summarized in Table 2:$\frac{\begin{matrix}{{{Mean}\quad{Number}\quad{of}\quad{fleas}\quad{on}\quad{Untreated}\quad{Cats}} -} \\{{Mean}\quad{Number}\quad{of}\quad{fleas}\quad{on}\quad{Treated}\quad{Cats}}\end{matrix}}{{Mean}\quad{Number}\quad{of}\quad{fleas}\quad{on}\quad{Untreated}\quad{Cats}} \times 100\%$

As shown in Table 2 the results demonstrate that the dosages used onGroups 2 and 3 are both effective at reducing the number of adult fleason cats through at least 29 days and thus are effective as a one monthdermal treatment. TABLE 3 Controlled Percent Reduction in FleaPopulation Day 1 Day 8 Day 15 Day 22 Day 29 Control 0 0 0 0 0 Group 1Group 2 100 100 99 99 96 Group 3 100 98 95 95 91

EXAMPLE 9 Preparation of Insecticide Formulation Containing DinotefuranDissolved in Ethyl Lactate

An insecticide formulation comprising the ingredients listed in Table 4at the concentrations indicated was prepared according to theillustrative method below. TABLE 4 Ingredient CAS # % (wt/wt)Olealkonium chloride 37139-99-4 1 Sodium dioctyl sulfosuccinate 577-11-71 Glycerol-polyethylene glycol 61788-85-0 7.5 oxystearate (hydrogenated)castor oil Vitamin E acetate 7695-91-2 2.5 n-Octyl pyrrolidone 2687-94-70.1 Ethyl lactate 97-64-3 48.6 Water (buffered)* Local Source 24.3Dinotefuran 165252-70-0 15 Total 100 pH 6.1*Water contains 0.2 M citric acid and 0.2 M sodium citrate buffersolution

Prepare 0.2M citric acid and 0.2M sodium citrate buffer solution in abeaker. Set aside. In a separate beaker add olealkonium chloride (10 g).Heat the solution to 50° C. with mixing. Add 75 g ofglycerol-polyethylene glycol oxystearate (hydrogenated) castor oil, 25 gVitamin E acetate, 10 g sodium dioctyl sulfosuccinate with continuousmixing at an increased speed as the mixture will be viscous. Once thesolution becomes homogeneous, add 486 g ethyl lactate. Adjust mixingspeed as needed. Add 243 g of the citric acid solution and then 150 gdinotefuran. Heat the solution to 40° C. until the dinotefurancompletely dissolves. Add 1 g n-octyl pyrrolidone. Cool the solution andmeasure the pH. The pH should be within 5.5-7.

The formulation described hereinabove is advantageous because of itsspeed-of-kill attribute, non-greasy appearance and excellent safetyprofile.

The percentage by weight of additives can be varied in the formulation.For example, the olealkonium choride can be from about 1-4%; the sodiumdioctyl sulfosuccinate can be from about 1-2%; the glycerol-polyethyleneglycol oxystearate castor oil can be from about 7.5-10% and the n-Octylpyrrolidone can be from about 0.1-2.0%. It will be readily appreciatedby the skilled artisan that the amount of ethyl lactate/water solventused in the formulation described herein will be adjusted accordingly toaccommodate increases or decreases in the amount of additive added tothe formulation.

It will thus be seen that the objects set forth above, among those madeapparent from the preceding description, are efficiently attained and,since certain changes may be made in carrying out the above method andin the composition set forth without departing from the spirit and scopeof the invention, it is intended that all matter contained in the abovedescription shall be interpreted as illustrative and not in a limitingsense.

It is also to be understood that the following claims are intended tocover all of the generic and specific features of the invention hereindescribed and all statements of the scope of the invention which, as amatter of language, might be said to fall therebetween.

Particularly it is to be understood that in said claims, ingredients orcompounds recited in the singular are intended to include compatiblemixtures of such ingredients wherever the sense permits.

1. An insecticide formulated by dissolving an insecticidably effectiveamount of dinotefuran in an effective amount of a solvent componentcomprising ethyl lactate to dissolve said dinotefuran.
 2. Theinsecticide of claim 1, wherein said dinotefuran is dissolved in theformulation to a concentration of about 5 to 25%.
 3. The insecticide ofclaim 1, wherein said dinotefuran is dissolved in the formulation to aconcentration of about 7 to 21%.
 4. The insecticide of claim 1, whereinsaid dinotefuran is dissolved in the formulation to a concentration ofabout 12 to 17%.
 5. The insecticide of claim 1, wherein said dinotefuranis dissolved in the formulation to a concentration of about 15%.
 6. Theinsecticide of claim 1, wherein said solvent component comprises overabout 35% ethyl lactate.
 7. The insecticide of claim 1, wherein saidsolvent component comprises 35-57% ethyl lactate.
 8. The insecticide ofclaim 1, wherein said solvent component comprises 42-53% ethyl lactate.9. The insecticide of claim 1, wherein said solvent component comprises47.5-50% ethyl lactate.
 10. The insecticide of claim 4, wherein saidsolvent component comprises 42-53% ethyl lactate.
 11. An insecticideformulated by dissolving an insecticidably effective amount of aninsecticidal (tetrahydro-3-furanyl) methylamine derivative in aneffective amount of a solvent component comprising sufficient ethyllactate to dissolve said insecticidably effective amount.
 12. Theinsecticide of claim 11, wherein said insecticidal derivative isdissolved in the formulation to a concentration of about 5 to 25%. 13.The insecticide of claim 11, wherein said insecticidal derivative isdissolved in the formulation to a concentration of about 7 to 21%. 14.The insecticide of claim 11, wherein said insecticidal derivative isdissolved in the formulation to a concentration of about 12 to 17%. 15.The insecticide of claim 11, wherein said solvent component comprisesover about 35% ethyl lactate.
 16. The insecticide of claim 11, whereinsaid solvent component comprises 35-57% ethyl lactate.
 17. Theinsecticide of claim 11, wherein said solvent component comprises 42-53%ethyl lactate.
 18. The insecticide of claim 11, wherein said solventcomponent comprises 47.5-50% ethyl lactate.
 19. The insecticide of claim14, wherein said solvent component comprises 42-53% ethyl lactate. 20.The insecticide of claim 11, wherein the solvent component consistsessentially of ethyl lactate and water.
 21. The insecticide of claim 1,wherein the formulation is not irritating to dogs or cats and iseffective to kill fleas with applications of less than 20 ml to a cat.22. The insecticide of claim 11, wherein the formulation is notirritating to dogs or cats and is effective to kill fleas withapplications of less than 20 ml to a cat.
 23. The insecticide of claim1, wherein 1.0 ml or less of the formulation is effective to kill fleason a cat for at least one month.
 24. The insecticide of claim 1, wherein0.4 ml or less of the formulation is effective to kill fleas on cat forat least one month.
 25. The insecticide of claim 11, wherein 1.0 ml orless of the formulation is effective to kill fleas on a cat for at leastone month.
 26. The insecticide of claim 11, wherein 0.4 ml or less ofthe formulation is effective to kill fleas on cat for at least onemonth.
 27. The insecticide of claim 1, comprising one or morefragrances, hair conditioners, spreading agents or UV protectants. 28.The insecticide of claim 1, comprising one or more fragrances, hairconditioners, spreading agents or UV protectants.
 29. A method ofcontrolling insect infestation in animals, comprising dissolvingdinotefuran in a solvent mixture consisting essentially of ethyl lactateand optionally water and applying an insecticidably effective amount ofthe solution to an animal.
 30. The method of claim 29, wherein theanimal is a cat or a dog.
 31. The method of claim 29, wherein the insectis a flea.